Treatment of benign prostatic hypertrophy

ABSTRACT

The administration of medrogestone is useful for treating the symptoms of benign prostatic hypertrophy.

United States Patent [191 Revesz TREATMENT OF BENIGN PROSTATIC HYPERTROPHY Inventor: Clara Revesz, Montreal, Quebec,

Canada Assignee: American Home Products Corporation, New York, NY.

Filed: Sept. 3, 1974 Appl. No.: 502,338

Related US. Application Data Continuation-in-part of Ser No. 442,270, Feb. 13, 1974, abandoned, which is a continuation of Ser. No. 259,707, June 5, I972, abandoned.

us. Cl. 424/242 Int. Cl A6lk 17/00 Field of Search 424/23s-243 June 10, 1975 [56] References Cited OTHER PUBLICATIONS Primary Examin'er-Shep K. Rose [5 7] ABSTRACT The administration of medrogestone is useful for treating the symptoms of benign prostatic hypertrophy.

1 Claim, No Drawings 1 TREATMENT OF BENIGN PROSTATIC HYPERTROPHY This Application is a continuation in part of my prior application Ser. No. 442,270, filed Feb. 13. 1974, now abandoned which is a continuation of my prior applica tion Ser. No. 259,707, filed June 5, 1972, now abandoned.

BACKGROUND OF THE INVENTION 1. Field of Invention This invention relates to a method for treating benign prostatic hypertrophy by the administration of the progestin, medrogestone.

2. Description of the Prior Art Benign prostatic hypertrophy is a common disorder which occurs spontaneously in man and dogs. In both species of these mammals the frequency of the condition increases with age. In the U.S. physicians have about three and one half million office visits per year from patients suffering from this disease. It has been reported regarding the incidence of this disease that (a) it occurs in 30 to 40% of males over 60 years old and (b) a 40 year old man has about a chance of developing this disease with obstruction requiring operative treatment before the age of 80. These and other studies, for example, see B. Lytton, et al., J. Urol. 99, 639 (1968), substantiate the fact that benign prostatic hypertrophy is a major problem.

For some time the accepted treatment of symptomatic urinary obstruction due to benign prostatic hypertrophy has been transurethral prostatectomy. Although such a surgical procedure is generally quite adequate for men in their fifties or sixties, such operations become less suitable for older men because of the increasing incidences of coincidental cardiac, renal or pulmonary complication. Estimations of the overall risk involved in this operation vary from less then 1% to more than 10%.

The need for an effective form of therapy is therefore undeniable.

Most of the past effort to develop new therapeutics have been based on the endocrine approach. The basis of this approach is that the growth and maintenance of the prostate is dependent on testicular homones. This theory is supported by the fact that benign prostatic hypertrophy has never been observed in the absence of testicular tissue, for example, it has never been diagnosed in eunuchs or men castrated before the age of 40. Moreover, in cases of prostatic atrophy such as pituitary infantilism, generation of the prostate gland occurs following administration of testosterone, interstitial cell stimulating hormone or human chorionic gonadotrophin. Animal experiments support this theory; however, the attainment of objective proof for this theory has yet to be obtained. For example, attempts to establish a difference in the chronological pattern of hormone secretion between normal males and patients with prostatic hypertrophy have not been successful to date.

In the past, several attempts have been made to treat benign prostatic hypertrophy with estrogens, androgens and combinations thereof. For the most part these attempts have not proven to be fully efficacious in providing meaningful remissions and cures.

More recently, progestins have been investigated as possible therapeutic agents for the treatment of this disorder. In 1965, J. Geller, et al., J. Amer. Med. Assoc., 193, 121 (1965), reported that large doses of the injectable progestin, l7a-hydroxyprogesterone caproate (3.0 g/week), afforded a clinical improvement in prostatism when given to ten patients with benign prostatic hypertrophy.

Following this report several clinicians investigated a variety of progestins, including l7a-hydroxyp rogesterone caproate, for their efficacy in treating this disorder. While some investigators reported apparently successful trials with some progestins, for example, mege strol acetate and 19-nor-17-hydroxyprogesterone caproate. others were singularly unsuccessful in finding any improvement in patients treated with certain other progestins including 17a-hydroxyprogesterone caproate; for example, see S.R. Weinberg, J. Urol., 100, 57 (1968). Undoubtedly, the variety of complex pharmacologic profiles encountered among different progestins and the inability of clinicians to obtain unequivocal and reproducible results adds to the difficulty of finding a suitable progestin for the treatment of benign prostatic hypertrophy.

Accordingly, upon review of the prior, generally inconsistent attempts to demonstrate the efficacy of drug treatment for benign prostatic hypertrophy, several prominent authorities have concluded that a search for suitable drug therapy in this case is in vain; for example, see J.P.B1andy, Br. Med. J.., 1, 31 (1971) and L, M. Franks in Pills for the Benign Prostrate," Proc. Roy. Soc. Med. 65, 125 (1972).

Notwithstanding the prior difficulties in finding a progestin for the treatment of benign prostatic hypertrophy l have surprisingly found that the progestin, medrogestone, is useful for such purposes.

Furthermore, the efficacy and safeness of the method of treating benign prostatic hypertrophy according to the disclosure of this invention is demonstrable in controlled, double blind, cross-over clinical studies. Especially noteworthy is the comparative safeness of the method and the relative lack of side effects such as overt signs of masculinization or feminization, or suppression of adrenal function often displayed by progestational agents.

SUMMARY OF THE INVENTION According to the method of this invention, medrogestone is administered to adult male humans or dogs having benign prostatic hypertrophy in amounts effective in reducing hypertrophy, whereby the symptoms and signs of urinary bladder neck obstruction from benign prostatic hypertrophy are alleviated and relieved.

DETAILED DESCRIPTION OF THE INVENTION 'The therapeutic agent of the invention, medrogestone, has the chemical structure, 6,17-dimethylpregna-4,6-diene3,20-dione, see R. Deghenghi et al., Tetrahedron, 19, 289 (1963). This agent has been described previously as a potent peroral progestin with antiandrogenic properties in laboratory animals, C. Revesz and C. I. Chappel, J. Reprod. Fertil., 12, 473 (1966). Recent clinical investigations have demonstrated its efficacy for the treatment of a variety of diseases. For example, W.F. Carter, et al., Amer. J. Obstet. Gynecol. 89, 635 (1964) found it to be effective for controlling dysfunctional uterine bleeding and GD. Malkasian, et al., Amer. J. Obstet. Gynecol. 110, 15 (1971 obtained objective responses when medrogestone was given to women afflicted with endometrial carcinoma.

-When the therapeutic agent of this invention is administered to mammals, namely humans or dogs, to relieve the symptoms of benign prostatic hypertrophy, it may be administered advantageously by the oral route although this mode of administration is not to be construed as limiting. For oral administration, the agent may be given alone, for example, the single active ingredient in a capsule, or it may be mixed with known pharmaceutically acceptable carriers and incorporated by known means into pharmaceutical preparations. Accordingly, the active ingredient may be given conveniently in a tablet prepared according to the known art in which it is compounded, for example, with a carrier such as lactose, a disintegrating agent such as starch and a lubricating agent such as magnesium stearate. For parenteral administration, the active ingredient may be dissolved or suspended in suitable sterile liquid carriers such as distilled water or oils of synthetic, animal, petroleum or vegetable origin, for example, soybean oil, sesame oil, mineral oil or propylene glycol. The usual preservatives and other ingredients used for pharmaceutical preparations for parenteral dose may also be incorporated.

The dosage of the present therapeutic agent for the method of this invention will vary with the particular form of administration and with the particular host, namely human or dog, under treatment. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In general, the therapeutic agent of this invention is most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects. In practice, a level that is in the range of about 0.015 to 5.0 mg/kg/day, is usually employed although as aforementioned variations will occur. However, a dosage level that is in the range of about 0.07 to 1.5 mg/kg/day is most desirably employed to achieve effective results. In other words, an adult male human weighing about 70 kg would receive a dosage from about 30 100 mg/day of medrogestone according to the most desirable embodiment of this invention.

1 The efficacy of the method of this invention has been determined clinically in a carefully controlled, double blind, cross-over study performed on 24 adult males, see R.E. Rangno, et al., Clin. Pharmacol. Therap., I2, 658 (1971).

In this study, 24 patients (mean age, 74 years) with benign prostatic hypertrophy were selected and assessed completely for control observations.

The patients were assigned randomly to one of the following two drug schedules: medrogestone, 50 mg.,

one b.i.d. for 24 weeks followed by placebo, one b.i.d. for 24 weeks; or a reverse schedule in which the placebo regimen preceded the medrogestone regimen.

The drug schedule assigned to a particular patient was unknown to both patient and physician until the study was concluded. w

Changes in the manifestation of benign prostatic hypertrophy were assessed in the following manner:

a. Initially and every three weeks during the study, an assessment was made of the patients performance during the three previous days regardingfrequency of urination, both day and night (nocturia), the presence or absence of intermittency, the length of time required to begin urination and the force and size of the urine stream.

b. Initially and every 12 weeks during the study, digital grading of the prostate +1 to +4), testicular length and radioactive residual urine were recorded. Residual bladder urine volume was calculated by a hippuran-l excretion technique, L. Rosenthall, Radiology, 80, 454 (I963).

c. Initially, and at the end of each 24 week treatment period, cystoscopy with prostatic needle biopsy and an intravenous pyelogram with postvoiding cystogram were performed.

In addition, hematologic, biochemical, hepatic, renal and thyroid function was monitored during the study.

Twenty patients completed the study. Two other patients died during the study from unrelated causes, one from an exacerbation of bronchitis with respiratory failure and the other died of heart failure. A third patient was excluded from the study after a final review showed that the patient had a urinary obstruction from urethral stricture rather than from benign prostatic hypertrophy and the fourth patient had to be dropped when he developed acute urinary retention requiring a transurethural resection.

The information from the twenty patients completing the study was pooled and statistically evaluated with regard to the efficacy of the method. I

For each parameter measured a simplified graded score was adapted whereby maximum improvement was graded as +1 and maximumworsening was graded as 1 as determined relative to the control value of zero indicative of no change. i

The data from the 20 patients was divided into two groups according to drug schedule. Group I included ten patients who received a period of placebo treatment P) followed by a period of medrogestone treatment (M Group II included the remaining ten patientswho received medrogestone treatment (M) followed by placebo treatment (P Table I shows the total scores for each group (i.e., the additive score of the ten patients in the group) obtained for each parameter measured at the end of each particlar treatment period with medrogestone or placebo.

TABLE I Continued Measurement Group l Group ll Treatment Total Treatment Total Period Score Period Score M 4.5 P 6.0 Intravenous P O M 4 pyelogram and M P -2 cystogram Cystoscopy P O M 6 M 4 P 2 Radioactive P 3.5 M 4.9 residual urine M 4.2 P 4.0 Total Patient P 0.6102 M 3.8106 Score M 3.9i0.6 P 3. 1:0.7

Difference in mean score between P and M significant (p 0,()l )v "Difference in mean score between P and M significant (p 0.0l "Difi'erence in mean score between P and P significant (p 0.0l )v In Group I the mean total score'after 24 weeks of placebo (P) for all nine measurements was increased an average of 6.6% to 0.6 I 0.2 out of a maximum score of nine. Improvement after 24 weeks of medrogestone (M is shown by an average increase of 43% in mean score to 3.9 i 0.6.

In Group II improvement after 24 weeks of medrogestone (M) is shown by an average increase of 42% in mean score to 3.8 i 0.6. At the end ofthe following placebo period (P some decrease in this initial improvement occurred but the score (3.1 i 0.7) at the end of this period was significantly greater than the score for those patients in Group I receiving the placebo first. This latter result is probably due to a carryover effect which lasted for at least 24 weeks after the discontinuation of the medrogestone therapy.

The three objective measurements, prostate size, cystogram and cystoscopy, all showed improvement during the medrogestone therapy. Further reduction of size of the prostate was noted in Group ll during the subsequent placebo period. In the five subjective measurements, frequency, nocturia, hesitancy, intermittency and force and size of the urine stream, major improvement was noted in all parameters. The reduction in the residual urine volumes for both groups during both treatment periods appeared to be similar; however. extremely wide individual variations in residual urine volumes were noted by this method throughout the study.

During the study no evidence of gynecomastia, change in body weight or testicular size was observed. Hematalogic. biochemical. hepatic. renal and thyroid function remained normal. Also no significant changes in plasma cortisol values or diurnal variation of plasma cortisol were noted. An increase in fasting blood sugar occurred in all six known diabetics included in the study, while receiving medrogestone. However. in all cases the blood sugar reverted to normal after the study. No evidence of carcinoma was observed.

The results of the preceding study clearly establishes that the administration of medrogestone is effective in alleviating the symptoms of benign prostatic hypertrophy in patients afflicted with such symptoms. Furthermore, medrogestone can be administered safely without causing overt signs of masculinization or feminization, or suppression of adrenal function.

The effectiveness of the agent of this invention in reducing the size of the prostate in the dog has been demonstrated in long term studies ranging from two and a half to six months in male beagle dogs receiving medrogestone by both the oral and intramuscular route. In one such study medrogestone was administered intramuscularly in 2.5 and 5.0 mg/kg doses, three times a week. A significant decrease of the prostate was noted without affecting the histology or weight of the testes. Similar results were obtained in dogs receiving a daily oral dose of 5 mg of medrogestone. No other related drug alterations were noted other than those expected from the pharmacologic activity of medrogestone. The results show that medrogestone is a useful and safe medicament for administration to dogs to prevent and alleviate the symptoms of benign prostatic hypertrophy.

I claim:

1. A method of treating a male human adult afflicted with the symptoms of benign prostatic hypertrophy which comprises administering orally to said male human adult an alleviating amount of from 30 to mg/day of medrogestone, daily, until statistically significant improved changes in the manifestation of symptoms of benign prostatic hypertrophy are obtained, without causing overt signs of masculinization, feminization or suppression of adrenal function. 

1. A METHOD OF TREATING A MALE HUMAN ADULT AFFLICTED WITH THE SYMPTOMS OF BENIGN PROSTATIC HYPERTROPHY WHICH COMPRISES ADMINISTERING ORALLY TO SAID MALE HUMAN ADULT AND ALLEVIATING AMOUNT OF FROM 30 TO 100 MG/DAY OF MEDROGESTONE, DAILY, UNTIL STATISTICALLY SIGNIFICANT IMPROVED CHANGES IN THE MANIFESTATION OF SYMPTOMS OF BENIGN PROSTATIC HYPERTROPHY ARE OBTAINED, WITHOUT CAUSING OVERT SIGNS OF MASCULINIZATION, FEMINIZATION OR SUPPRESSION OF ADRENAL FUNCTION. 